tbuckley/cabot-search huggingface dataset:
P050: Reed-Sternberg cells accelerate glycolytic and mitochondrial metabolism of tumor microenvironment cells
Authors: Michał Kurlapski, Maciej Szydłowski, Alicja Braczko, Marika Frańczak, Maciej Zieliński, Ryszard Smoleński, Przemysław Juszczyński, Jan Maciej Zaucha
Journal: HemaSphere (2022)

Figure 1: Phenotype of isolated from fine-needle biopsy lymph node aspirate, peripheral blood of patients diagnosed with HL and from peripheral blood of a healthy donor cells. Results of Seahorse analysis of studied cell populations. Cancer cells in Hodgkin’s lymphoma [HL] account for only a few % of the tumor mass which mainly consists of normal cells of the immune system including macrophages. Macrophages may perform different functions depending on the signals they receive. Tumor-associated macrophages (TAM) are often polarized towards the M2-like phenotype - immunosuppressive phenotype, preferring oxygen metabolism, and their presence in HL is associated with a worse prognosis. HL is highly avid in positron emission tomography, which suggests that glucose (Glc) metabolism is increased in non-cancerous microenvironmental cells. Here we asked if and what type of glucose metabolism is increased in TAMs and monocytes/Cd14+ cells. The project was conducted on the in vitro and the ex vivo model. In the in vitro model, the studied populations were THP-1 monocytic macrophages stimulated by Reed-Sternberg [RS] cells, and control macrophages that were not subjected to stimulation. In the ex vivo model, CD14+ cells were isolated, using the immunomagnetic method, from: fine-needle biopsy lymph node aspirate, peripheral blood of patients diagnosed with HL and from peripheral blood of a healthy donor. The cell’s phenotype was determined by flow cytometry using CD14, CD16, CD163, CD206, CD68, CD11b, HLA-DR, PDL1 antibodies. Glc metabolism of the studied cell populations was analyzed using the Seahorse XFp analyser [by directly measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR)]. The in vitro model experiment showed the intensification of Glc metabolism, in both glycolysis and oxidative phosphorylation pathways, in cells that have been stimulated by RS cells compared to control macrophages. Comparable results were obtained in the ex vivo model, which corroborates the reliability of the in vitro model. Glucose metabolism increases not only the population of cells obtained from lymph node aspirate but also from peripheral blood of patients diagnosed with HL, which may indicate both paracrine and endocrine neoplastic cells impact. Our data indicate that RS cells stimulate Glc metabolism of tumor microenvironment and peripheral blood CD14+ cells through both glycolysis and oxidative phosphorylation pathways.
T020: Interim PET-guided treatment of early-stage nodular lymphocyte-predominant Hodgkin lymphoma: a subgroup analysis of the GHSG HD16 and HD17 studies
Authors: Dennis A. Eichenauer, Ina Bühnen, Michael Fuchs, Richard Greil, Alden Moccia, Josée. M. Zijlstra, Sylvia Hartmann, Carsten Kobe, Markus Dietlein, Andreas Engert, Peter Borchmann
Journal: HemaSphere (2022)

Background: The optimal treatment for patients with early-stage nodular-lymphocyte predominant Hodgkin lymphoma (NLPHL) other than stage IA is undefined. Patients and Methods: We investigated characteristics and outcomes of patients with early-stage NLPHL (favorable: 85 patients; unfavorable: 15 patients) who had treatment within the randomized GHSG HD16 and HD17 studies. Results were compared to those from patients with classical Hodgkin lymphoma (cHL) (favorable: 495 patients; unfavorable: 764 patients) treated within the same studies. Chemotherapy consisted of 2 cycles of ABVD (HD16) or 2 cycles of escalated BEACOPP plus 2 cycles of ABVD („2 + 2“) (HD17). In the experimental study arms, consolidation radiotherapy (RT) was applied on the basis of the result of interim positron emission tomography (PET-2). In the standard arms, consolidation RT was mandatory. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: In the HD16 and HD17 studies, 62/85 (73%) and 13/15 (87%) NLPHL patients were male as compared to 254/495 (51%) and 337/764 (44%) cHL patients. The median age of patients with NLPHL was 37 years in the HD16 study (cHL: 36 years) and 42 years in the HD17 study (cHL: 31 years). The majority of NLPHL patients included in the HD16 and HD17 studies presented with a typical histopathological growth pattern (HD16: 66%; HD17: 70%) The 5-year PFS for all NLPHL patients was 90.3% (cHL: 90.8%) in the HD16 study and 92.9% (cHL: 95.7%) in the HD17 study. In the HD16 study, the 5-year PFS for the subgroup of PET-2-positive NLPHL patients was 89.3% (cHL: 91.6%); PET-2-negative NLPHL patients had a 5-year PFS of 91.0% (cHL: 90.4%). For PET-2-negative NLPHL patients assigned to the chemotherapy only arm, the 5-year PFS was 83.0% (cHL: 88.2%) whereas PET-2-negative NLPHL patients treated with chemotherapy plus RT had a 5-year PFS of 100% (cHL: 92.3%) (p=0.05). Subgroup analyses according to the PET-2 result were not conducted for NLPHL patients treated within the HD17 study due to the small number of individuals with NLPHL histology included in this trial. The 5-year OS for NLPHL patients treated within the HD16 and HD17 studies was 100% (cHL: 98.6% in HD16; 99.2% in HD17). Conclusion: Contemporary HL-directed treatment results in excellent 5-year outcomes for patients with newly diagnosed early-stage NLPHL and should thus be considered as valid approach for this patient group.
P018: Treatment outcomes in classical Hodgkin lymphoma (HL): 5-year update report from the Brazilian Prospective Registry
Authors: Irene Biasoli, Nelson Castro, Carolina Colaço. Villarim, Fabiola Traina, Carlos Sergio Chiattone, Monica Praxedes, Cristiana Solza, Leila Perobelli, Otavio Baiocchi, Rafael Gaiolla, Carla Boquimpani, Valeria Buccheri, Caroline Bonamin Sola, Roberta Oliveira De Paula E. Silva, Ana Carolina Ribas, Giovana Steffenello, Katia Pagnano, Andrea Soares, Samuel Souza Medina, Talita Silveira, Karin Zattar Cecyn, Lilian Goveia, Leonardo Carvalho Palma, Mariana De Oliveira Marques, Carmino De Souza, Nelson Spector
Journal: HemaSphere (2022)

Introduction: Data about HL in developing countries are scarce. In 2009, a HL prospective registry was launched in Brazil. Methods: The first analysis was presented with patients (pts) diagnosed from 2009 to 2014. Here we present an updated analysis with pts diagnosed until 2018 and a median follow-up of 5 years. Results: A total of 1357 pts with HIV negative classical HL were registered from January 2009 to December, 2018. 28 pts were excluded for various reasons, leaving 1329 pts for this analysis. Median age was 30 y/o (13–90). Females comprised 50%. The median time from onset of symptoms to diagnosis was 6 (0–60) months. 862 (65%) had advanced disease. Stage IVB was present in 28%, and a high-risk IPS score in 40%. Comparing pts included from 2009–2014 and 2015–2018, there was an increase in the use of PET for staging (11% vs 36%, P<.0001) and for end-of-treatment (40% vs 79%, P<.0001). ABVD was the first-line treatment in 94% of pts. 34 pts (2.6%) died during the first treatment. Radiotherapy (RT) was used in 72% of pts with limited, 59% with intermediate, and 28% with advanced disease. There was a reduction in the use of RT (44% vs 35%, P=.002) from 2009–2014 to 2015–2018. This reduction was higher in advanced disease (32% vs 24%, P=0.01). The 5-year progression-free survival (PFS) and 5-year overall survival (OS) were 70% and 86%, respectively. The 5-year PFS in limited, intermediate, and advanced disease were 97%, 82%, and 62% (P<.0001), respectively. The 5-year OS for limited, intermediate and advanced disease were 100%, 94%, and 80% (P<.0001), respectively. The impact of socioeconomic status (SES) on outcomes was analyzed in pts treated with ABVD. The 5-year PFS in higher and lower SES were 75% and 60% (P<.0001). The 5-year OS in higher and lower SES were 90% and 77% (P<0.0001). The fatality ratio during treatment was 5.0% and 1.1% for lower and higher SES (P<0.0001). After adjustments for potential confounders, lower SES remained independently associated with poorer survival (HR 2.10 [1.52–2.90] for OS and HR 1.58 [1.26–1.99] for PFS). Conclusions: This analysis confirmed the predominance of advanced disease and high-risk profile pts. There was an increase in the use of PET and a reduction in RT in recent years. We confirmed that the outcomes are 10–15% lower in Brazil than reported in the literature. SES was an independent factor associated with shorter survival.
P023: PET2-adapted approach after 2 cycles of ABVD is comparable to 2 cycles of BEACOPP escalated and 2 cycles of ABVD and irradiation in early unfavorable Hodgkin lymphoma
Authors: Heidi Mocikova, Jana Markova, Lubica Gaherova, Maria Maco, Alice Sýkorová, David Belada, Marie Lukášová, Vit Prochazka, Juraj Duras, Tomas Kozak
Journal: HemaSphere (2022)

Background: PET2-adapted approach after 2 cycles of ABVD reduced treatment intensity in the majority of patients with early stages of classical Hodgkin lymphoma (cHL) according to EORTC H10 trial. GHSG HD17 enabled omission of radiotherapy in PET4-negative early unfavorable HL treated with 2 cycles of BEACOPP escalated and 2 cycles of ABVD (2 + 2 chemotherapy). We compared PET2-adapted approach with 2 + 2 chemotherapy followed by 30 Gy of involved-node radiotherapy (INRT) regardless of interim PET in patients with early unfavorable cHL assessed according to the GHSG risk factors. Methods: Overall, 224 patients with early unfavorable cHL (aged 18–60 years) prospectively observed in the Czech Hodgkin Lymphoma Study Group Registry between 2003–2021 were analyzed. Patients in clinical stage IIB with massive mediastinal tumor and/or with extranodal disease were excluded. Overall, 194 patients received 2 + 2+INRT chemotherapy and 30 patients were treated with PET2-adapted approach: 29 PET2-negative patients received 4 cycles of ABVD and 30 Gy of INRT and one PET2-positive patient was treated with 2 cycles of ABVD plus 2 cycles of BEACOPP escalated and 30 Gy INRT. Results: Median age at the time of cHL diagnosis was 32 (range 18–59) years. Median follow-up was longer in the 2 + 2+INRT group (98.9, range 6.2–211.7) months compared to the PET2-adapted approach (30.8, range 9.8–90.4) months. The 2-year progression-free survival and 2-year overall survival did not differ between two groups (99.5% [95% CI 98.5%–100%]) and 100% [95% CI 100%–100%]), respectively. The rate of patients with neutropenia grade 3 and anemia grade 3 did not differ significantly between both groups (p=0.09 and p=0.60, respectively). Thrombocytopenia was more frequent in the 2 + 2+INRT group (p0.001). Grade 3 non-hematological toxicity occurred in 3 patients in the 2 + 2+INRT group (2 infections, 1 deep vein thrombosis). Conclusion: This retrospective analysis indicates that there is no superiority in progression-free survival and overall survival when comparing 2 + 2 chemotherapy and INRT to PET2-adapted approach. The toxicity is higher in the 2 + 2+INRT group. This work was supported by the following grants AZV NU22-03–00182 from the Ministry of Health of the Czech Republic and Cooperatio Program awarded by the Charles University in Prague in the Czech Republic.
CXCL13 chemokine is a novel player in multiple myeloma osteolytic microenvironment, M2 macrophage polarization, and tumor progression
Authors: Katia Beider, Valeria Voevoda-Dimenshtein, Ali Zoabi, Evgenia Rosenberg, Hila Magen, Olga Ostrovsky, Avichai Shimoni, Lola Weiss, Michal Abraham, Amnon Peled, Arnon Nagler
Journal: Journal of Hematology & Oncology (2022)

We assessed the mechanism by which multiple myeloma (MM) shapes the bone marrow (BM) microenvironment and affects MΦ polarization.In vivo xenograft model of BM-disseminated human myeloma, as well as analysis of MM cell lines, stromal components, and primary samples from patients with MM, was utilized.Analysis of the BM from MM-bearing mice inoculated with human CXCR4-expressing RPMI8226 cells revealed a significant increase in M2 MΦ cell numbers (p < 0.01). CXCL13 was one of the most profoundly increased factors upon MM growth with increased levels in the blood of MM-bearing animals. Myeloid cells were the main source of the increased murine CXCL13 detected in MM-infiltrated BM. MM cell lines induced CXCL13 and concurrent expression of M2 markers (MERTK, CD206, CD163) in co-cultured human MΦ in vitro. Interaction with MΦ reciprocally induced CXCL13 expression in MM cell lines. Mechanistically, TGFβ signaling was involved in CXCL13 induction in MM cells, while BTK signaling was implicated in MM-stimulated increase of CXCL13 in MΦ. Recombinant CXCL13 increased RANKL expression and induced TRAP+ osteoclast (OC) formation in vitro, while CXCL13 neutralization blocked these activities. Moreover, mice inoculated with CXCL13-silenced MM cells developed significantly lower BM disease. Reduced tumor load correlated with decreased numbers of M2 MΦ in BM, decreased bone disease, and lower expression of OC-associated genes. Finally, higher levels of CXCL13 were detected in the blood and BM samples of MM patients in comparison with healthy individuals.Altogether, our findings suggest that bidirectional interactions of MΦ with MM tumor cells result in M2 MΦ polarization, CXCL13 induction, and subsequent OC activation, enhancing their ability to support bone resorption and MM progression. CXCL13 may thus serve as a potential novel target in MM.
Leveraging Implementation Science for Cardiovascular Health Equity: A Scientific Statement From the American Heart Association
Authors: Nathalie Moise, Crystal W. Cené, Rachel G. Tabak, Deborah R. Young, Katherine T. Mills, Utibe R. Essien, Cheryl A.M. Anderson, Francisco Lopez-Jimenez
Journal: Circulation (2022)

Reducing cardiovascular disease disparities will require a concerted, focused effort to better adopt evidence-based interventions, in particular, those that address social determinants of health, in historically marginalized populations (ie, communities excluded on the basis of social identifiers like race, ethnicity, and social class and subject to inequitable distribution of social, economic, physical, and psychological resources). Implementation science is centered around stakeholder engagement and, by virtue of its reliance on theoretical frameworks, is custom built for addressing research-to-practice gaps. However, little guidance exists for how best to leverage implementation science to promote cardiovascular health equity. This American Heart Association scientific statement was commissioned to define implementation science with a cardiovascular health equity lens and to evaluate implementation research that targets cardiovascular inequities. We provide a 4-step roadmap and checklist with critical equity considerations for selecting/adapting evidence-based practices, assessing barriers and facilitators to implementation, selecting/using/adapting implementation strategies, and evaluating implementation success. Informed by our roadmap, we examine several organizational, community, policy, and multisetting interventions and implementation strategies developed to reduce cardiovascular disparities. We highlight gaps in implementation science research to date aimed at achieving cardiovascular health equity, including lack of stakeholder engagement, rigorous mixed methods, and equity-informed theoretical frameworks. We provide several key suggestions, including the need for improved conceptualization and inclusion of social and structural determinants of health in implementation science, and the use of adaptive, hybrid effectiveness designs. In addition, we call for more rigorous examination of multilevel interventions and implementation strategies with the greatest potential for reducing both primary and secondary cardiovascular disparities.
Impaired Myocardial Mitochondrial Respiration in Humans With Prediabetes: A Footprint of Prediabetic Cardiomyopathy
Authors: Elric Zweck, Daniel Scheiber, Heinz-Peter Schultheiss, Oliver Kuss, Malte Kelm, Michael Roden, Ralf Westenfeld, Julia Szendroedi
Journal: Circulation (2022)
Eating away T cell responses in lung cancer
Authors: Roberto Ferrara, Luca Roz
Journal: The Journal of Experimental Medicine (2022)

Despite evidence for clinical benefit in patients suffering from lung cancer following treatment with immune checkpoint inhibitors (ICI), it is still uncertain how to predict which patients are likely to experience a significant response. In their work, Valencia et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220726) identify the DSTYK kinase as a cancer cell–intrinsic modulator of response to immunotherapy. Through regulation of the mTOR pathway and stimulation of protective autophagy, DSTYK blunts CD8+ T cell–mediated killing of cancer cells. Accordingly, lung cancers with increased expression of DSTYK are less responsive to ICI treatment. These observations could be useful in the clinic towards the development of predictive biomarkers and novel therapeutic strategies.
Wnt Signaling in the Phenotype and Function of Tumor-Associated Macrophages
Authors: Megan L. Tigue, Matthew A. Loberg, Jeremy A. Goettel, William A. Weiss, Ethan Lee, Vivian L. Weiss
Journal: Cancer Research (2022)

Abstract Tumor-associated macrophages (TAM) play an important role in supporting tumor growth and suppressing antitumor immune responses, and TAM infiltration has been associated with poor patient prognosis in various cancers. TAMs can be classified as pro-inflammatory, M1-like, or anti-inflammatory, M2-like. While multiple factors within the tumor microenvironment affect the recruitment, polarization, and functions of TAMs, accumulating evidence suggests that Wnt signaling represents an important, targetable driver of an immunosuppressive, M2-like TAM phenotype. TAM production of Wnt ligands mediates TAM-tumor cross-talk to support cancer cell proliferation, invasion, and metastasis. Targeting TAM polarization and the protumorigenic functions of TAMs through inhibitors of Wnt signaling may prove a beneficial treatment strategy in cancers where macrophages are prevalent in the microenvironment.
MNX1-AS1 Promotes Phase Separation of IGF2BP1 to Drive c-Myc–Mediated Cell-Cycle Progression and Proliferation in Lung Cancer
Authors: Qingqing Zhu, Chongguo Zhang, Tianyu Qu, Xiyi Lu, Xuezhi He, Wei Li, Dandan Yin, Liang Han, Renhua Guo, Erbao Zhang
Journal: Cancer Research (2022)

Abstract c-Myc and E2F1 play critical roles in many human cancers. As long noncoding RNAs (lncRNA) are known to regulate various tumorigenic processes, elucidation of mechanisms of cross-talk between lncRNAs and c-Myc/E2F1-related signaling pathways could provide important insights into cancer biology. In this study, we used integrated bioinformatic analyses and found that the lncRNA MNX1-AS1 is upregulated in non–small cell lung cancer (NSCLC) via copy-number gain and c-Myc–mediated transcriptional activation. High levels of MNX1-AS1 were associated with poor clinical outcomes in patients with lung cancer. MNX1-AS1 promoted cell proliferation and colony formation in vitro and tumor growth in vivo. MNX1-AS1 bound and drove phase separation of IGF2BP1, which increased the interaction of IGF2BP1 with the 3′-UTR (untranslated region) of c-Myc and E2F1 mRNA to promote their stability. The c-Myc/MNX1-AS1/IGF2BP1 positive feedback loop accelerated cell-cycle progression and promoted continuous proliferation of lung cancer cells. In a lung cancer patient-derived xenograft model, inhibition of MNX1-AS1 suppressed cancer cell proliferation and tumor growth. These findings offer new insights into the regulation and function of c-Myc and E2F1 signaling in NSCLC tumorigenesis and suggest that the MNX1-AS1/IGF2BP1 axis may serve as a potential biomarker and therapeutic target in NSCLC. Significance: MNX1-AS1 drives phase separation of IGF2BP1 to increase c-Myc and E2F1 signaling and to activate cell-cycle progression to promote proliferation in NSCLC.
The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
Authors: Giovanni Gambi, Gabrielle Mengus, Guillaume Davidson, Ewout Demesmaeker, Alessandro Cuomo, Tiziana Bonaldi, Vicky Katopodi, Gabriel G. Malouf, Eleonora Leucci, Irwin Davidson
Journal: Cancer Research (2022)

Abstract Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression. Significance: The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells.
Author Correction: Performance of plasma phosphorylated tau 181 and 217 in the community
Authors: Michelle M. Mielke, Jeffrey L. Dage, Ryan D. Frank, Alicia Algeciras-Schimnich, David S. Knopman, Val J. Lowe, Guojun Bu, Prashanthi Vemuri, Jonathan Graff-Radford, Clifford R. Jack, Ronald C. Petersen
Journal: Nature Medicine (2022)
Bioessential Inorganic Molecular Wire‐Reinforced 3D‐Printed Hydrogel Scaffold for Enhanced Bone Regeneration
Authors: Jin Woong Lee, Sudong Chae, Seungbae Oh, Dai‐Hwan Kim, Si Hyun Kim, Seung Jae Kim, Jae‐Young Choi, Jung Heon Lee, Si Young Song
Journal: Advanced Healthcare Materials (2022)

Materials with physicochemical properties and biological activities similar to those of the natural extracellular matrix are in high demand in tissue engineering. In particular, Mo3 Se3- inorganic molecular wire (IMW) is a promising material composed of bioessential minerals and possess nanometer-scale diameters, negatively charged surfaces, physical flexibility, and nanotopography characteristics, which are essential for interactions with cell membrane proteins. Here, an implantable 3D Mo3 Se3- IMW enhanced gelatin-GMA/silk-GMA hydrogel (IMW-GS hydrogel) is developed for osteogenesis and bone formation, followed by biological evaluations. The mechanical properties of the 3D printed IMW-GS hydrogel are improved by noncovalent interactions between the Mo3 Se3- IMWs and the positively charged residues of the gelatin molecules. Long-term biocompatibility with primary human osteoblast cells (HOBs) is confirmed using the IMW-GS hydrogel. The proliferation, osteogenic gene expression, collagen accumulation, and mineralization of HOBs improve remarkably with the IMW-GS hydrogel. In in vivo evaluations, the IMW-GS hydrogel implantation exhibits a significantly improved new bone regeneration of 87.8 ± 5.9% (p < 0.05) for 8 weeks, which is higher than that from the gelatin-GMA/silk-GMA hydrogel without Mo3 Se3- IMW. These results support a new improved strategy with in vitro and in vivo performance of 3D IMW enhanced scaffolds in tissue engineering.